The drug 1-.beta.-D-arabinofuranosylcytosine (araC) is a nucleoside analog which has proven useful as a chemotherapeutic agent in the clinical treatment of certain types of cancer. It has also been used as an antiviral agent. In a similar manner, the drug 9-.beta.-D-arabinofuranosyladenine (araA) has been found useful. A third drug, 4-amino-7Hpyrrolo[2,3-d]pyrimidine (tubercidin), although exhibiting high toxicity in many instances, has been shown to be extremely effective in the treatment of basal skin carcinoma when the drug is localized topically on the lesion.
There are several problems in chemotherapy with the arabinonucleosides araC and araA. The first is their rapid catabolism via deaminase enzymes to ineffective metabolites. In the case of araC, high levels of deoxycytidine deaminase exist in the liver of humans, and the ineffective metabolite 1-.beta.-D-arabinofuranosyluracial (araU) appears rapidly in human urine after injection of araC. Due to this degradation, the half-life of araC in humans has been estimated to be only 3 to 9 minutes. The second problem is the eventual resistance developed by the cells. In experimental tumor systems, this resistance has been attributed to the selection of cells in which the deoxynucleoside kinases have a low specific activity compared to the wild type, so that the arabinoside is not metabolized to the 5'-triphosphate, the actual cytotoxic metabolite. A third problem is the toxicity of the arabinonucleosides in rapidly dividing normal tissue as well as against neoplastic cell types.
One approach to circumvent these drawbacks involves the attachment of drugs to a nontoxic "carrier molecule" that protects the drug from degradation. Subsequently, the drug is released by enzymatic or chemical action. A particular example utilizes lipophilic fatty acid esters such as 5'-O-adamantoyl-araC, 5'-O-palmitoyl-araC, and 5'-O-valeryl-araA as molecular depots or target "prodrugs" of the parent arabinonucleoside. Such derivatives protected the parent drug from catabolic degradation, however, in vivo studies have indicated no therapeutic advantages of 5'-O-palmitoyl-araC, presumably due to poor drug absorption. Recently, there has been some indication of improved efficacy, relative to araC, of corticosteroid-araC conjugates and promising preliminary antitumor data have been reported.
Since the effectiveness of the enzymes which act to release a particular drug from a prodrug is influenced by the particular carrier, it is of interest to provide prodrugs with different carriers. It is also of interest to provide prodrugs based on a mixture of different carriers. However, it is not always possible to prepare new prodrugs utilizing known techniques and it becomes necessary to develop new methods to achieve the desired compounds in reasonably pure form.
Accordingly, one object of this invention is the preparation and use of new prodrugs based on phospholipid-drug conjugates. A second object of the invention is the preparation and use of prodrugs based on different phospholipid carriers. A third object of the invention is to prepare such phospholipid-drug conjugates with different types of linkages between the phospholipid moiety and the drug. Another object of the invention is the development of a method for preparing new prodrugs. Yet another object of the invention is related to new compositions of matter useful as prodrugs. An additional object is the preparation of new prodrugs in pure form. A further object is the preparation of phospholipid-drug conjugates as new prodrugs in which the phospholipid moiety exists as a single optical isomer, namely that which is commonly found in nature, the L form. Such single diastereomers are likely to be the preferred substrates for the enzymes responsible for release of the drug from the prodrug. These and other objects will become apparent from the following description.